Indole-amid derivatives which possess glycogen phosphorylase inhibitory activity

ABSTRACT

Heterocyclic amides of formula (1)  
                 
wherein: m is 0, 1 or 2; n is 0, 1 or 2; B is phenyl or heterocyclyl; 
         R 1  is selected from for example halo, nitro, cyano, hydroxy, carboxy;    R 2  and R 3  are independently selected from, for example, C 5-7 cycloalkyl, cyano(C 1-4 )alkyl, C 1-4 alkyl (optionally substituted with 1 or 2 R 8  groups), OR 8  and R 8 ;    R 4  is independently selected from for example hydrogen, halo, nitro, cyano, hydroxy, C 1-4 alkyl, and C 1-4 alkanoyl;    R 8  is selected from for example hydroxy, heterocyclyl, aryl, —COCOOR 9 , —C(O)N(R 9 )(R 10 ), (R 9 )(R 10 )N— and —COOR 9 ;    R 9  and R 10  are selected from for example hydrogen, hydroxy, C 1-4 alkyl (optionally substituted by 1 or 2 R 13 );    R 13  is selected from for example, hydroxy, C 1-4 alkoxy, heterocyclyl and C 1-4 alkanoyl;    R 14  is selected from for example, hydrogen, halo, C 1-4 alkyl, C 5-7 cycloalkyl, C 1-4 alkoxy, cyano, cyano(C 1-4 )alkyl, —COR 3 , (R 2 )(R 3 )NCO—, and (R 2 )(R 3 )NSO 2 —; or a pharmaceutically acceptable salt or pro-drug thereof; possess glycogen phosphorylase inhibitory activity and accordingly have value in the treatment of disease states associated with increased glycogen phosphorylase activity. Processes for the manufacture of said heterocyclic amide derivatives and pharmaceutical compositions containing them are described.

This application is a national stage filing under 35 U.S.C. 371 ofInternational Application No. PCT/GB03/00924, filed Mar. 4, 2003, whichclaims priority from United Kingdom Patent Application No. 0205175.3,filed Mar. 6, 2002, the specification of which is incorporated byreference herein. International Application No. PCT/GB03/00924 waspublished under PCT Article 21(2) in English.

The present invention relates to heterocyclic amide derivatives,pharmaceutically acceptable salts and in vivo hydrolysable estersthereof. These heterocyclic amide derivatives possess glycogenphosphorylase inhibitory activity and accordingly have value in thetreatment of disease states associated with increased glycogenphosphorylase activity and thus are potentially useful in methods oftreatment of a warm-blooded animal such as man. The invention alsorelates to processes for the manufacture of said heterocyclic amidederivatives, to pharmaceutical compositions containing them and to theiruse in the manufacture of medicaments to inhibit glycogen phosphorylaseactivity in a warm-blooded animal such as man.

The liver is the major organ regulating glycaemia in the post-absorptivestate. Additionally, although having a smaller role in the contributionto post-prandial blood glucose levels, the response of the liver toexogenous sources of plasma glucose is key to an ability to maintaineuglycaemia. An increased hepatic glucose output (HGO) is considered toplay an important role in maintaining the elevated fasting plasmaglucose (FPG) levels seen in type 2 diabetics; particularly those with aFPG >140 mg/dl (7.8 mM). (Weyer et al, (1999), J Clin Invest 104:787-794; Clore & Blackgard (1994), Diabetes 43: 256-262; De Fronzo, R.A., et al, (1992) Diabetes Care 15; 318 - 355; Reaven, G. M. (1995)Diabetologia 38; 3-13).

Since current oral, anti-diabetic therapies fail to bring FPG levels towithin the normal, non-diabetic range and since raised FPG (andglycHbA1c) levels are risk factors for both macro- (Charles, M. A. et al(1996) Lancet 348, 1657-1658; Coutinho, M. et al (1999) Diabetes Care22; 233-240; Shaw, J. E. et al (2000) Diabetes Care 23, 34-39) andmicro-vascular disease (DCCT Research Group (1993) New. Eng. J. Med.329; 977-986); the reduction and normalisation of elevated FPG levelsremains a treatment goal in type 2 DM.

It has been estimated that, after an overnight fast, 74% of HGO wasderived from glycogenolysis with the remainder derived fromgluconeogenic precursors (Hellerstein et al (1997) Am J Physiol, 272:E163). Glycogen phosphorylase is a key enzyme in the generation byglycogenolysis of glucose-1-phosphate, and hence glucose in liver andalso in other tissues such as muscle and neuronal tissue.

Liver glycogen phosphorylase a activity is elevated in diabetic animalmodels including the db/db mouse and the fa/fa rat (Aiston S et al(2000). Diabetalogia 43, 589-597).

Inhibition of hepatic glycogen phosphorylase with chloroindoleinhibitors (CP91149 and CP320626) has been shown to reduce both glucagonstimulated glycogenolysis and glucose output in hepatocytes (Hoover etal (1998) J Med Chem 41, 2934-8; Martin et al (1998) PNAS 95, 1776-81).Additionally, plasma glucose concentration is reduced, in a dose relatedmanner, db/db and ob/ob mice following treatment with these compounds.

Studies in conscious dogs with glucagon challenge in the absence andpresence of another glycogen phosphorylase inhibitor, Bay K 3401, alsoshow the potential utility of such agents where there is elevatedcirculating levels of glucagon, as in both Type 1 and Type 2 diabetes.In the presence of Bay R 3401, hepatic glucose output and arterialplasma glucose following a glucagon challenge were reduced significantly(Shiota et al, (1997), Am J Physiol, 273: E868).

The heterocyclic amides of the present invention possess glycogenphosphorylase inhibitory activity and accordingly are expected to be ofuse in the treatment of type 2 diabetes, insulin resistance, syndrome X,hyperinsulinaemia, hyperglucagonaemia, cardiac ischaemia and obesity,particularly type 2 diabetes.

According to one aspect of the present invention there is provided acompound of formula (1):

wherein:

-   -   n is 0, 1 or 2;    -   m is 0, 1 or2;    -   R¹ is independently selected from hydrogen, halo, nitro, cyano,        hydroxy, amino, carboxy, carbamoyl, N—C₁₋₄alkylcarbamoyl,        N,N—(C₁₋₄alkyl)₂carbamoyl, sulphamoyl, N—C₁₋₄alkylsulphamoyl,        NN—(C₁₋₄alkyl)₂sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,        C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino,        N,N—(C₁₋₄alkyl)₂amino, hydroxyC₁₋₄alkyl, fluoromethyl,        difluoromethyl, trifluoromethyl, trifluoromethoxy and groups of        the formula A or A′:        wherein x is 0 or 1, r is 0, 1, 2 or 3, s is 1 or 2 and u is 1        or 2; provided that the hydroxy group is not a substituent on        the ring carbon adjacent to the ring oxygen;    -   R⁴ is independently selected from hydrogen, halo, nitro, cyano,        hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl,        trifluoromethoxy, carboxy, carbamoyl, C₁₋₄alkyl, C₂₋₄alkenyl,        C₂₋₄alkynyl, C₁₋₄alkoxy and C₁₋₄alkanoyl;    -   B is phenyl or heterocyclyl;    -   R¹⁴ is selected from hydrogen, halo, C₁₋₄alkyl (optionally        substituted by 1 or 2 hydroxy groups), C₅₋₇cycloalkyl        (optionally substituted with 1 or 2 hydroxy groups), C₁₋₄alkoxy,        cyano, cyano(C₁₋₄)alkyl, —COR³, (R²)(R³)NCO—, and (R²)(R³)NSO₂—;    -   R² and R³ are independently selected from C₅₋₇cycloalkyl        (optionally substituted with 1 or 2 hydroxy groups),        cyano(C₁₋₄)alkyl, 5- and 6-membered cyclic acetals and mono- and        di-methyl derivatives thereof, tetrahydrothiopyranyl,        1-oxotetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl,        fluoromethylcarbonyl, difluoromethylcarbonyl,        trifluoromethylcarbonyl, C₁₋₄alkyl (optionally substituted with        1 or 2 R⁸ groups), —OR⁸ and R⁸;    -   R⁸ is independently selected from hydrogen,        2,2-dimethyl-1,3-dioxolan-4-yl, heterocyclyl (optionally        substituted on ring carbon or ring nitrogen by 1 or 2 groups        selected from hydrogen, nitro, halo, cyano, hydroxy and        C₁₋₄alkyl), (heterocyclyl)C₁₋₄alkyl (wherein the heterocyclyl is        optionally substituted on ring carbon or ring nitrogen by 1 or 2        groups selected from hydrogen, nitro, halo, cyano, hydroxy and        C₁₋₄alkyl), aryl (optionally substituted by 1 or 2 groups        selected from nitro, halo, cyano, hydroxy and C₁₋₄alkyl),        C₁₋₄alkyl, C₂₋₄alkenyl, cyclo(C₃₋₈)alkyl, C₁₋₄alkoxy,        cyano(C₁₋₄)alkyl, amino(C₁₋₄)alkyl (optionally substituted on        nitrogen by 1 or 2 groups selected from hydrogen, C14alkyl,        hydroxy, hydroxy(C₁₋₄)alkyl, dihydroxy(C₁₋₄)alkyl, aryl and        aryl(C₁₋₄)alkyl), C₁₋₄alkylS(O)_(c)(C₁₋₄)alkyl (wherein c is 0,        1 or 2), —N(OH)CHO, —CH₂CH(CO₂R⁹)N(R⁹R¹⁰), —CH₂OR⁹, (R⁹)(R¹⁰)N—,        —COOR⁹, —CH₂COOR⁹, —CH₂CONR⁹R¹⁰ and —(CH₂)_(u)CH(NR⁹R¹⁰)CO₂R⁹        (wherein u is 1, 2 or 3);    -   R⁹ and R¹⁰ are independently selected from hydrogen, hydroxy,        C₁₋₄alkyl (optionally substituted by 1 or 2 hydroxy groups),        C₅₋₇cycloalkyl (optionally substituted by 1 or 2 hydroxy        groups), C₂₋₄alkenyl, cyano(C₁₋₄)alkyl, tetrahydrothiopyranyl,        1-oxotetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl,        2,2-dimethyl-1,3-dioxolan-4-yl, aryl (optionally substituted by        1 or 2 substituents selected from hydrogen, nitro, halo, hydroxy        and C₁₋₄alkyl) and C₁₋₄alkyl substituted by R¹³; or R⁹ and R¹⁰        together with the nitrogen to which they are attached form a 4-        to 6-membered ring where the ring is optionally substituted on        carbon by 1 or 2 substituents selected from oxo, hydroxy,        carboxy, halo, nitro, nitroso, cyano, isocyano, amino,        N—C₁₋₄alkylamino, N,N—(C₁₋₄alkyl)₂amino, carbonyl, C₁₋₄alkoxy,        heterocyclyl, C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(f)(C₁₋₄)alkyl        (wherein f is 0, 1 or 2), —N(OH)CHO, (R¹¹)(R¹²)NCO—,        (R¹¹)(R¹²)NSO₂—, —COCH₂OR¹¹ and (R¹¹)(R¹²)N—;    -   R¹³ is selected from hydroxy, C₁₋₄alkoxy, heterocyclyl,        C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(d) (wherein d is 0, 1 or 2),        —N(OH)CHO, —C(O)N(R¹¹)(R¹²), (R¹¹)(R¹²)NSO₂—, —COCH₂OR¹¹ and        (R¹¹)(R¹²)N—;    -   R¹¹ and R¹² are independently selected from hydrogen, C₁₋₄alkyl,        C₁₋₄alkoxy, hydroxyC₁₋₄alkyl and C₁₋₄alkylS(O)_(e) (wherein e is        0, 1 or 2);    -   or a pharmaceutically acceptable salt or pro-drug thereof.

According to another aspect of the present invention there is provided acompound of formula (1) wherein:

-   -   n is 0, 1 or 2;    -   m is 0, 1 or2;    -   R¹ is independently selected from hydrogen, halo, nitro, cyano,        hydroxy, amino, carboxy, carbamoyl, N—C₁₋₄alkylcarbamoyl,        N,N—(C₁₋₄alkyl)₂carbamoyl, sulphamoyl, N—C₁₋₄alkylsulphamoyl,        NN—(C₁₋₄alkyl)2sulphamoyl, sulfino, sulfo, C₁₋₄alkyl,        C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl,        C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino,        hydroxyC₁₋₄alkyl, fluoromethyl, difluoromethyl, trifluoromethyl,        trifluoromethoxy and R¹ is of the formula A or A′:        wherein x is 0 or 1, r is 0, 1, 2 or 3 and s is 1 or 2; provided        that the hydroxy group is not a substituent on the ring carbon        adjacent to the ring oxygen;    -   R⁴ is independently selected from hydrogen, halo, nitro, cyano,        hydroxy, amino, carboxy, carbamoyl, N—C₁₋₄alkylcarbamoyl,        NN—(C₁₋₄alkyl)₂carbamoyl, sulphamoyl, N—C₁₋₄alkylsulphamoyl,        NN—(C₁₋₄alkyl)2sulphamoyl, sulfino, sulfo, C₁₋₄alkyl,        C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl,        C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino,        hydroxyC₁₋₄alkyl, fluoromethyl, difluoromethyl, trifluoromethyl        and trifluoromethoxy;    -   B is phenyl or heterocyclyl;    -   R¹⁴ is selected from hydrogen, halo, C₁₋₄alkyl (optionally        substituted by 1 or 2 hydroxy groups provided that when there        are 2 hydroxy groups they are not substituents on the same        carbon), C₅₋₇cycloalkyl (optionally substituted with 1 or 2        hydroxy groups provided that when there are 2 hydroxy groups        they are not substituents on the same carbon), C₁₋₄alkoxy,        cyano, cyano(C₁₋₄)alkyl, —COR³, (R²)(R³)NCO—, and (R²)(R³)NSO₂—;    -   {R² and R³ are independently selected from C₁₋₄alkyl        (substituted by 1 or 2 hydroxy groups provided that when there        are 2 hydroxy groups they are not substituents on the same        carbon), C₅₋₇cycloalkyl (optionally substituted with 1 or 2        hydroxy groups provided that when there are 2 hydroxy groups        they are not substituents on the same carbon), cyano(C₁₋₄)alkyl,        4-butanolidyl, 5-pentanolidyl, tetrahydrothiopyranyl,        1-oxotetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl,        fluoromethylcarbonyl, difluoromethylcarbonyl,        trifluoromethylcarbonyl, C₁₋₄alkyl (substituted by R⁸), OR⁸ and        R⁸;    -   [wherein R⁸ is independently selected from hydrogen,        2,2-dimethyl-1,3-dioxolan-4-yl, heterocyclyl (optionally        substituted on ring carbon or ring nitrogen by 1 or 2 groups        selected from hydrogen, nitro, halo, cyano, hydroxy and        C₁₋₄alkyl), (heterocyclyl)C₁₋₄alkyl (wherein the heterocyclyl is        optionally substituted on ring carbon or ring nitrogen by 1 or 2        groups selected from hydrogen, nitro, halo, cyano, hydroxy and        C₁₋₄alkyl), aryl (optionally substituted by 1 or 2 groups        selected from nitro, halo, cyano, hydroxy and C₁₋₄alkyl),        C₁₋₄alkyl, C₂₋₄alkenyl, cyclo(C₃₋₈)alkyl, C₁₋₄alkoxy,        cyano(C₁₋₄)alkyl, amino(C₁₋₄)alkyl (optionally substituted on        nitrogen by 1 or 2 groups selected from hydrogen, C₁₋₄alkyl,        hydroxy, hydroxy(C₁₋₄)alkyl, dihydroxy(C₁₋₄)alkyl, aryl and        aryl(C₁₋₄)alkyl), C₁₋₄alkylS(O)_(c)(C₁₋₄)alkyl (wherein c is 0,        1 or 2), —N(OH)CHO, —CH₂CH(CO₂R⁹)N(R⁹R¹⁰), —CH₂OR⁹, (R⁹)(R¹⁰)N—,        —COOR⁹, —CH₂COOR⁹ , —CH₂CONR⁹R¹⁰ and {CH₂)_(u)CH(NR⁹R¹⁰)CO₂R⁹        (wherein u is 1, 2 or 3);    -   (wherein R⁹ and R¹⁰ are independently selected from hydrogen,        hydroxy, C₁₋₄alkyl (optionally substituted by 1 or 2 hydroxy        groups provided that when there are 2 hydroxy groups they are        not substituents on the same carbon), C₅₋₇cycloalkyl (optionally        substituted by 1 or 2 hydroxy groups provided that when there        are 2 hydroxy groups they are not substituents on the same        carbon), C₂₋₄alkenyl, cyano(C₁₋₄)alkyl, 4-butanolidyl,        5-pentanolidyl, tetrahydrothiopyranyl,        1-oxotetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl,        2,2-dimethyl-1,3-dioxolan-4-yl, aryl (optionally substituted by        1 or 2 substituents selected from hydrogen, nitro, halo, hydroxy        and C₁₋₄alkyl) and C ₄alkyl substituted by R¹³    -   {wherein R¹³ is selected from hydroxy, C₁₋₄alkoxy, heterocyclyl,        C₁₋₄alkanoyl, C₁₋₄alkylS(O)_(d) (wherein d is 0, 1 or 2),        —N(OH)CHO, (R¹¹)(R¹²)NCO—, (R¹¹)(R¹²)NSO₂—, —COCH₂OR¹¹,        (R¹¹)(R¹²)N—;    -   [wherein R¹¹ and R¹² are independently selected from hydrogen,        C₁₋₄alkyl, C₁₋₄alkoxy, hydroxyC₁₋₄alkyl, C₁₋₄alkylS(O)_(e)        (wherein e is 0, 1 or 2)]}; and    -   R⁹ and R¹⁰ can together with the nitrogen to which they are        attached form 4- to 6-membered ring where the ring is optionally        substituted on carbon by 1 or 2 substituents selected from oxo,        hydroxy, carboxy, halo, nitro, nitroso, cyano, isocyano, amino,        N—C₁₋₄alkylamino, N,N—(C₁₋₄alkyl)₂amino, carbonyl, sulfo,        C₁₋₄alkoxy, heterocyclyl, C₁₋₄alkanoyl,        C₁₋₄alkylS(O)_(f)(C₁₋₄)alkyl (wherein f is 0, 1 or 2),        —N(OH)CHO, (R¹¹)(R¹²)NCO—, (R¹¹)(R¹²)NSO₂—, —COCH₂OR¹¹,        (R¹¹)(R¹²)N—;    -   wherein R¹¹ and R¹² are as defined above)]};    -   or a pharmaceutically acceptable salt or in vivo hydrolysable        ester thereof.

It is to be understood that, where optional substitution on alkyl orcycloalkyl groups in R², R³, R⁹, R¹⁰, R¹⁴ (as defined hereinbefore orhereinafter) allows two hydroxy substituents on the alkyl or cycloalkylgroup, or one hydroxy substituent and a second substituent linked by aheteroatom (for example alkoxy), then these two substituents are notsubstituents on the same carbon atom of the alkyl or cycloalkyl group.

In another aspect, the invention relates to compounds of formula (1) ashereinabove defined or to a pharmaceutically acceptable salt.

In another aspect, the invention relates to compounds of formula (1) ashereinabove defined or to a pro-drug thereof. Suitable examples ofpro-drugs of compounds of formula (1) are in-vivo hydrolysable esters ofcompounds of formula (1). Therefore in another aspect, the inventionrelates to compounds of formula (I) as hereinabove defined or to anin-vivo hydrolysable ester thereof.

It is to be understood that, insofar as certain of the compounds offormula (1) defined above may exist in optically active or racemic formsby virtue of one or more asymmetric carbon atoms, the invention includesin its definition any such optically active or racemic form whichpossesses glycogen phosphorylase inhibition activity. The synthesis ofoptically active forms may be carried out by standard techniques oforganic chemistry well known in the art, for example by synthesis fromoptically active starting materials or by resolution of a racemic form.Similarly, the above-mentioned activity may be evaluated using thestandard laboratory techniques referred to hereinafter.

Within the present invention it is to be understood that a compound ofthe formula (1) or a salt thereof may exhibit the phenomenon oftautomerism and that the formulae drawings within this specification canrepresent only one of the possible tautomeric forms. It is to beunderstood that the invention encompasses any tautomeric form which hasglycogen phosphorylase inhibition activity and is not to be limitedmerely to any one tautomeric form utilised within the formulae drawings.The formulae drawings within this specification can represent only oneof the possible tautomeric forms and it is to be understood that thespecification encompasses all possible tautomeric forms of the compoundsdrawn not just those forms which it has been possible to showgraphically herein.

It is also to be understood that certain compounds of the formula (1)and salts thereof can exist in solvated as well as unsolvated forms suchas, for example, hydrated forms. It is to be understood that theinvention encompasses all such solvated forms which have glycogenphosphorylase inhibition activity.

It is also to be understood that certain compounds of the formula (1)may exhibit polymorphism, and that the invention encompasses all suchforms which possess glycogen phosphorylase inhibition activity.

The present invention relates to the compounds of formula (1) ashereinbefore defined as well as to the salts thereof. Salts for use inpharmaceutical compositions will be pharmaceutically acceptable salts,but other salts may be useful in the production of the compounds offormula (1) and their pharmaceutically acceptable salts.Pharmaceutically acceptable salts of the invention may, for example,include acid addition salts of the compounds of formula (1) ashereinbefore defined which are sufficiently basic to form such salts.Such acid addition salts include for example salts with inorganic ororganic acids affording pharmaceutically acceptable anions such as withhydrogen halides (especially hydrochloric or hydrobromic acid of whichhydrochloric acid is particularly preferred) or with sulphuric orphosphoric acid, or with trifluoroacetic, citric or maleic acid.Suitable salts include hydrochlorides, hydrobromides, phosphates,sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates,acetates, benzoates, citrates, maleates, fumarates, succinates, lactatesand tartrates. In addition where the compounds of formula (1) aresufficiently acidic, pharmaceutically acceptable salts may be formedwith an inorganic or organic base which affords a pharmaceuticallyacceptable cation. Such salts with inorganic or organic bases includefor example an alkali metal salt, such as a sodium or potassium salt, analkaline earth metal salt such as a calcium or magnesium salt, anammonium salt or for example a salt with methylamine, dimethylamine,trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

The compounds of the invention may be administered in the form of apro-drug which is broken down in the human or animal body to give acompound of the invention. A prodrug may be used to alter or improve thephysical and/or pharmacokinetic profile of the parent compound and canbe formed when the parent compound contains a suitable group orsubstituent which can be derivatised to form a prodrug. Examples ofpro-drugs include in-vivo hydrolysable esters of a compound of theinvention or a pharmaceutically-acceptable salt thereof.

Various forms of prodrugs are known in the art, for examples see:

-   -   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985)        and Methods in Enzymology, Vol. 42, p. 309-396, edited by K.        Widder, et al. (Academic Press, 1985);    -   b) A Textbook of Drug Design and Development, edited by        Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and        Application of Prodrugs”, by H. Bundgaardp. 113-191 (1991);    -   c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);    -   d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77,        285 (1988); and    -   e) N. Kakeya, et al., Chem Pharm Bull,32, 692 (1984).

An in vivo hydrolysable ester of a compound of formula (1) containingcarboxy or hydroxy group is, for example a pharmaceutically acceptableester which is cleaved in the human or animal body to produce the parentacid or alcohol.

Suitable pharmaceutically acceptable esters for carboxy include

-   -   C₁₋₆alkoxymethyl esters for example methoxymethyl,        C₁₋₆alkanoyloxymethyl esters for example pivaloyloxymethyl,        phthalidyl esters,    -   C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example        1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters        for example 5-methyl-1,3-dioxolen-2-onylmethyl; and        C₁₋₆alkoxycarbonyloxyethyl esters for example        1-methoxycarbonyloxyethyl and may be formed at any carboxy group        in the compounds of this invention.

Suitable pharmaceutically-acceptable esters for hydroxy includeinorganic esters such as phosphate esters (including phosphoramidiccyclic esters) and α-acyloxyalkyl ethers and related compounds which asa result of the in-vivo hydrolysis of the ester breakdown to give theparent hydroxy group/s. Examples of α-acyloxyalkyl ethers includeacetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection ofin-vivo hydrolysable ester forming groups for hydroxy includeC₁₋₁₀alkanoyl, for example acetyl; benzoyl; phenylacetyl; substitutedbenzoyl and phenylacetyl, C₁₋₁₀alkoxycarbonyl (to give alkyl carbonateesters), for example ethoxycarbonyl; di-(C₁₋₄)alkylcarbamoyl andN-(di-(C₁₋₄)alkylaminoethyl)-N—(C₁₋₄)alkylcarbamoyl (to givecarbamates); di-(C₁₋₄)alkylaminoacetyl and carboxyacetyl. Examples ofring substituents on phenylacetyl and benzoyl include aminomethyl,(C₁₋₄)alkylaminomethyl and di-((C₁₋₄)alkyl)aminomethyl, and morpholinoor piperazino linked from a ring nitrogen atom via a methylene linkinggroup to the 3- or 4-position of the benzoyl ring. Other interestingin-vivo hydrolysable esters include, for example,RAC(O)O(C₁₋₆)alkyl-CO—, wherein RA is for example,benzyloxy-(C₁₋₄)alkyl, or phenyl). Suitable substituents on a phenylgroup in such esters include, for example,4-(C₁₋₄)piperazino-(C₁₋₄)alkyl, piperazino-(C₁₋₄)alkyl andmorpholino-(C₁-C₄)alkyl.

In this specification the generic term “alkyl” includes bothstraight-chain and branched-chain alkyl groups. However references toindividual alkyl groups such as “propyl” are specific for the straightchain version only and references to individual branched-chain alkylgroups such as t-butyl are specific for the branched chain version only.For example, “C₁₋₄alkyl” includes methyl, ethyl, propyl, isopropyl andt-butyl. An analogous convention applies to other generic terms, forexample “C₂₋₄alkenyl” includes vinyl, allyl and 1-propenyl and“C₂₋₄alkynyl” includes ethynyl, 1-propynyl and 2-propynyl.

The term “hydroxyC₁₋₄alkyl” includes hydroxymethyl, hydroxyethyl,hydroxypropyl, hydroxyisopropyl and hydroxybutyl. The term“hydroxyethyl” includes 1-hydroxyethyl and 2-hydroxyethyl. The term“hydroxypropyl” includes 1-hydroxypropyl, 2-hydroxypropyl and3-hydroxypropyl and an analogous convention applies to terms such ashydroxybutyl. The term “dihydroxyC₁₋₄alkyl” includes dihydroxyethyl,dihydroxypropyl, dihydroxyisopropyl and dihydroxybutyl. The term“dihydroxypropyl” includes 1,2-dihydroxypropyl and 1,3-dihydroxypropyl.An analogous convention applies to terms such as dihydroxyisopropyl anddihydroxybutyl.

The term “halo” refers to fluoro, chloro, bromo and iodo. The term“dihaloC₁₋₄alkyl” includes difluoromethyl and dichloromethyl. The term“trihaloC₁₋₄alkyl” includes trifluoromethyl.

Examples of “5- and 6-membered cyclic acetals and mono- and di-methylderivatives thereof” are:

-   -   1,3-dioxolan-4-yl, 2-methyl-1,3-dioxolan4-yl,        2,2-dimethyl-1,3-dioxolan4-yl; 2,2-dimethyl-1,3-dioxan4-yl;        2,2-dimethyl-1,3-dioxan-5-yl; 1,3-dioxan-2-yl.

The term “sulfo” means HOSO₂—. The term “sulfino” means HO₂S—.

Examples of “C₁₋₄alkoxy” include methoxy, ethoxy, propoxy andisopropoxy. Examples of “C₁₋₄alkanoyl” include formyl, acetyl andpropionyl. Examples of “C₁₋₄alkanoyloxy” are formyloxy, acetoxy andpropionoxy. Examples of “N—(C₁₋₄alkyl)amino” include methylamino andethylamino. Examples of “N,N—(C₁₋₄alkyl)₂amino” includeN—N-(methyl)₂amino, N—N-(ethyl)₂amino and N-ethyl-N-methylamino.Examples of “N—(C₁₋₄alkyl)carbamoyl” are methylcarbamoyl andethylcarbamoyl. Examples of “N,N—(C₁₋₄alkyl)₂carbamoyl” areN,N-(methyl)₂carbamoyl, N,N-(ethyl)₂carbamoyl andN-methyl-N-ethylcarbamoyl. Examples of “N—(C₁₋₄alkyl)sulphamoyl” areN-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of“N,N—(C₁₋₄alkyl)2sulphamoyl” are N,N-(methyl)₂sulphamoyl,NN-(ethyl)₂sulphamoyl and N-(methyl)-N-(ethyl)sulphamoyl.

Examples of “cyano(C₁₋₄)alkyl” are cyanomethyl, cyanoethyl andcyanopropyl. Examples of “C₅₋₇cycloalkyl” are cyclopentyl, cyclohexyland cycloheptyl. Examples of “C₃₋₈cycloalkyl” ” and “C₃₋₇cycloalkyl”include “C₅₋₇cycloalkyl, cyclopropyl, cyclobutyl and cyclooctyl.

The term “aminoC₁₋₄alkyl” includes aminomethyl, aminoethyl, aminopropyl,aminoisopropyl and aminobutyl. The term “aminoethyl” includes1-aminoethyl and 2-aminoethyl. The term “aminopropyl” includes1-aminopropyl, 2-aminopropyl and 3-aminopropyl and an analogousconvention applies to terms such as aminoiospropyl and aminobutyl.

Examples of “C₁₋₄alkylS(O)_(c) (wherein c is 0 to 2)”,“C₁₋₄alkylS(O)_(d) (wherein d is 0 to 2)”, “C₁₋₄alkylS(O)_(e) (wherein eis 0 to 2)”, and “C₁₋₄alkylS(O)_(f) (wherein f is 0 to 2)” independentlyinclude methylthio, ethylthio, propylthio, methanesulphinyl,ethanesulphinyl, propanesulphinyl, mesyl, ethanesulphonyl,propanesulphonyl and isopropanesulphonyl.

Where optional substituents are chosen from “0, 1, 2 or 3” groups it isto be understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups. An analogous conventionapplies to substituents chose from “0, 1 or 2” groups and “1 or 2”groups.

“Heterocyclyl” is a saturated, partially saturated or unsaturated,optionally substituted monocyclic ring containing 5 to 7 atoms of which1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen,which may, unless otherwise specified, be carbon or nitrogen linked,wherein a —CH₂— group can optionally be replaced by a —C(O)-and a ringsulphur atom may be optionally oxidised to form the S-oxide(s). Examplesand suitable values of the term “heterocyclyl” are morpholino,morpholinyl, piperidino, piperidyl, pyridyl, pyranyl, pyrrolyl,imidazolyl, thiazolyl, thienyl, dioxolanyl, thiadiazolyl, piperazinyl,isothiazolidinyl, triazolyl, tetrazolyl, pyrrolidinyl, 2-oxazolidinonyl,5-isoxazolonyl, thiomorpholino, pyrrolinyl, homopiperazinyl,3,5-dioxapiperidinyl, 3-oxopyrazolin-5-yl, tetrahydropyranyl,tetrahydrothiopyranyl, 1-oxotetrahydrothiopyranyl,1,1-dioxotetrahydrothiopyranyl, pyrimidyl, pyrazinyl, pyridazinyl,pyrazolyl, pyrazolinyl, isoxazolyl, 4-oxopyridyl, 2-oxopyrrolidyl,4-oxothiazolidyl, furyl, thienyl, oxazolyl, and oxadiazolyl. Preferably“heterocyclyl” is morpholino, morpholinyl, piperidino, piperidyl,pyridyl, pyranyl, pyrrolyl, imidazolyl, thiazolyl, thienyl,thiadiazolyl, piperazinyl, isothiazolidinyl, 1,3,4-triazolyl,tetrazolyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl,3,5-dioxapiperidinyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,pyrazolinyl, isoxazolyl, 4-oxopyridyl, 2-oxopyrrolidyl,4-oxothiazolidyl, furyl, thienyl, oxazolyl, 1,3,4-oxadiazolyl, and1,2,4-oxadiazolyl. More preferably “heterocyclyl” is oxazolyl,1,2,4-oxadiazolyl, pyridyl, furyl, thienyl, morpholine, pyrazinyl andpiperazinyl.

Suitable optional substituents for “heterocyclyl” as a saturated orpartially saturated ring are 1, 2 or 3 substituents independentlyselected from halo, cyano, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy andC₁₋₄alkylS(O)_(b) (wherein b is 0, 1 or 2). Further suitablesubstituents for “heterocyclyl” as a saturated or partially saturatedring are 1, 2 or 3 substituents independently selected from fluoro,chloro, cyano, hydroxy, methyl, ethyl, methoxy, methylthio,methylsulfinyl and methylsulfonyl.

Suitable optional susbtituents for “heterocyclyl” as an unsaturated ringare 1, 2 or 3 substituents independently selected from halo, cyano,nitro, amino, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylS(O)_(b) (whereinb is 0, 1 or 2), N—(C₁₋₄alkyl)amino and N,N—(C₁₋₄alkyl)₂amino. Furthersuitable optional susbtituents for “heterocyclyl” as an unsaturated ringare 1, 2 or 3 substituents independently selected from fluoro, chloro,cyano, nitro, amino, methylamino, dimethylamino, hydroxy, methyl, ethyl,methoxy, methylthio, methylsulfinyl and methylsulfonyl.

Examples of “(heterocyclyl)C₁₋₄alkyl” are morpholinomethyl,morpholinethyl, morpholinylmethyl, morpholinylethyl, piperidinomethyl,piperidinoethyl, piperidylmethyl, piperidylethyl, imidazolylmethyl,imidazolylethyl, oxazolylmethyl, oxazolylethyl, 1,3,4-oxadiazolylmethyl,1,2,4-oxadiazolylmethyl, 1,2,4-oxadiazolylethyl, pyridylmethyl,pyridylethyl, furylmethyl, furylethyl, (thienyl)methyl, (thienyl)ethyl,pyrazinylmethyl, pyrazinylethyl, piperazinylmethyl and piperazinylethyl.

Examples of “aryl” are optionally substituted phenyl and naphthyl.

Examples of “aryl(C₁₋₄)alkyl” are benzyl, 2-phenylethyl, naphthylmethyland naphthylethyl.

Suitable optional substituents for “aryl” groups are 1, 2 or 3substituents independently selected from halo, cyano, nitro, amino,hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylS(O)_(b) (wherein b is 0, 1 or2), N—(C₁₋₄alkyl)amino and N,N—(C₁₋₄alkyl)₂amino. Further suitableoptional susbtituents for “aryl” groups are 1, 2 or 3 substituentsindependently selected from fluoro, chloro, cyano, nitro, amino,methylamino, dimethylamino, hydroxy, methyl, ethyl, methoxy, methylthio,methylsulfinyl and methylsulfonyl.

Preferred values of B, R¹, R⁴, R¹⁴, m and n are as follows. Such valuesmay be used where appropriate with any of the definitions, claims orembodiments defined hereinbefore or hereinafter.

In one embodiment of the invention are provided compounds of formula(1), in an alternative embodiment are providedpharmaceutically-acceptable salts of compounds of formula (1), in afurther alternative embodiment are provided in-vivo hydrolysable estersof compounds of formula (1), and in a further alternative embodiment areprovided pharmaceutically-acceptable salts of in-vivo hydrolysableesters of compounds of formula (1).

In one aspect of the invention n is 0 or 1.

Preferably n is 1.

In another aspect of the present invention R¹ is selected from hydrogen,halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl,trifluoromethyl and groups of the formula A or A′:

wherein x is 0 or 1, r is 0, 1, 2 or 3, s is 1 or 2 and u is 1 or 2;provided that the hydroxy group is not a substituent on the ring carbonadjacent to the ring oxygen;

Preferably R¹ is hydrogen or halo.

More preferably R¹ is hydrogen, chloro or fluoro.

In one aspect of the invention B is phenyl.

In another aspect of the invention B is heterocyclyl.

Preferably B is selected from phenyl, pyridyl, pyrimidinyl, pyrrolyl,thienyl, furyl, oxazole, isoxazole and oxadiazole.

In one aspect of the invention R¹⁴ is selected from hydrogen, halo,C₁₋₄alkyl (optionally substituted by 1 or 2 hydroxy groups),C₅₋₇cycloalkyl (optionally substituted with 1 or 2 hydroxy groups),C₁₋₄alkoxy, cyano, cyano(C₁₋₄)alkyl, —COR³, (R²)(R³)NCO—, and(R²)(R³)NSO₂—;

-   -   wherein R₂ and R₃ are independently selected from C₁₋₄alkyl        (substituted by 1 or 2 hydroxy groups), C₅₋₇cycloalkyl        (optionally substituted with 1 or 2 hydroxy), cyano(C₁₋₄)alkyl,        fluoromethylcarbonyl, difluoromethylcarbonyl,        trifluoromethylcarbonyl, C₁₋₄alkyl (substituted by R⁸), OR⁸ and        R⁸;    -   wherein R⁸ is independently selected from hydrogen, furyl        (optionally substituted on carbon by 1 or 2 nitro groups),        thienyl (optionally substituted on carbon by 1 or 2 nitro        groups), morpholino, furyl(C₁₋₄)alkyl (wherein furyl is        optionally substituted on carbon by 1 or 2 nitro groups),        thienyl(C₁₋₄)alkyl (wherein thienyl is optionally substituted on        carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl,        imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl,        tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl,        phenyl (optionally substituted by 1 or 2 groups selected from        nitro, halo, cyano, hydroxy and C₁₋₄alkyl), pyrazinyl,        4-methylpiperazino, piperazinyl, C₁₋₄alkyl, C₂₋₄alkenyl,        cyclo(C₃₋₈)alkyl, C₁₋₄alkoxy, cyano(C₁₋₄)alkyl, amino(C₁₋₄)alkyl        (optionally substituted on nitrogen by 1 or 2 groups selected        from hydrogen, C₁₋₄alkyl, hydroxy, hydroxy(C₁₋₄)alkyl,        dihydroxy(C₁₋₄)alkyl, aryl and aryl(C₁₋₄)alkyl),        C₁₋₄alkylS(O)_(c)(C₁₋₄)alkyl (wherein c is 0, 1 or 2),        —CH₂CH(CO₂R⁹)N(R⁹R¹⁰), —CH₂OR⁹, (R⁹)(R¹⁰)N—, —COOR⁹ and        —CH₂COOR⁹ , —CH₂CONR⁹R¹⁰, —CH₂CH₂CH(NR⁹R¹⁰)CO₂R⁹;    -   wherein R⁹ and R¹⁰ are independently selected from hydrogen,        C₁₋₄alkyl (optionally substituted by 1 or 2 hydroxy groups),        C₅₋₇cycloalkyl (optionally substituted by 1 or 2 hydroxy        groups), C₂₋₄alkenyl, cyano(C₁₋₄)alkyl, phenyl (optionally        substituted by 1 or 2 groups selected from nitro, halo, hydroxy        and cyano) and C₁₋₄alkyl substituted by R¹³; or    -   R⁹ and R¹⁰ together with the nitrogen to which they are attached        form 4- to 6-membered ring where the ring is optionally        substituted on carbon by 1 or 2 substituents selected from oxo,        hydroxy, carboxy, halo, nitro, nitroso, cyano, isocyano, amino,    -   N—C₁₋₄alkylamino, NN—(C₁₋₄)₂alkylamino, carbonyl, C₁₋₄alkoxy,        heterocyclyl, C₁₋₄alkanoyl, and C₁₋₄alkylS(O)_(f)(C₁₋₄)alkyl        (wherein f is 0, 1 or 2);    -   wherein R¹³ is selected from C₁₋₄alkoxy, furyl (optionally        substituted on carbon by 1 or 2 nitro groups), thienyl        (optionally substituted on carbon by 1 or 2 nitro groups),        morpholino, furyl(C₁₋₄)alkyl (wherein furyl is optionally        substituted on carbon by 1 or 2 nitro groups),        thienyl(C₁₋₄)alkyl (wherein thienyl is optionally substituted on        carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl,        imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl,        tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl,        phenyl (optionally substituted by 1 or 2 groups selected from        nitro, halo, cyano, hydroxy and C₁₋₄alkyl), pyrazinyl,        piperazinyl, C₁₋₄alkylS(O)_(d)(C₁₋₄)alkyl (wherein d is 0, 1 or        2);    -   wherein R¹¹ is selected from hydrogen, C ₄alkyl, C₁₋₄alkoxy,        hydroxyC₁₋₄alkyl, C₁₋₄alkylS(O)_(e) (wherein e is 0, 1 or 2).

In a further aspect of the invention R¹⁴ is selected from hydrogen,—COR³, (R²)(R³)NCO—, and (R²)(R³)NSO₂—;

-   -   wherein R² and R³ are independently selected from C₁₋₄alkyl        (substituted by 1 or 2 hydroxy groups), fluoromethylcarbonyl,        difluoromethylcarbonyl, trifluoromethylcarbonyl,    -   C₁₋₄alkyl (substituted by R⁸), OR⁸ and R⁸;    -   wherein R⁸ is independently selected from hydrogen, furyl        (optionally substituted on carbon by 1 or 2 nitro groups),        thienyl (optionally substituted on carbon by 1 or 2 nitro        groups), morpholino, furyl(C₁₋₄)alkyl (wherein furyl is        optionally substituted on carbon by 1 or 2 nitro groups),        thienyl(C₁₋₄)alkyl (wherein thienyl is optionally substituted on        carbon by 1 or 2 nitro groups), phenyl (optionally substituted        by 1 or 2 groups selected from nitro, halo, cyano and hydroxy),        C₂₋₄alkenyl, cyclo(C₃₋₈)alkyl, cyano(C₁₋₄)alkyl,        amino(C₁₋₄)alkyl (optionally substituted on nitrogen by 1 or 2        groups selected from hydrogen, C₁₋₄alkyl, hydroxy,        hydroxy(C₁₋₄)alkyl, dihydroxy(C₁₋₄)alkyl, aryl and        aryl(C₁₋₄)alkyl), ClalkylS(O)_(c)(C₁₋₄)alkyl (wherein c is 0, 1        or 2), —CH₂CH(CO₂R⁹)N(R⁹R¹⁰), —CH₂OR⁹, (R⁹)(R¹⁰)N—, —COOR⁹,        —CH₂COOR⁹, —CH₂CONR⁹R¹⁰, and —CH₂CH₂CH(NR⁹R¹⁰)CO₂R⁹;    -   wherein R⁹ and R¹⁰ are independently selected from hydrogen,        C₁₋₄alkyl (optionally substituted by 1 or 2 hydroxy groups),        C₂₋₄alkenyl, cyano(C₁₋₄)alkyl and phenyl (optionally substituted        by 1 or 2 groups selected from nitro, halo, hydroxy and cyano).

In another aspect of the invention R¹⁴ is selected from hydrogen, —COR³,(R²)(R³)NCO—, and (R²)(R³)NSO₂—;

-   -   wherein R² and R³ are independently selected from C₁₋₄alkyl        (substituted by R⁸), OR⁸ and R⁸;    -   wherein R⁸ is independently selected from hydrogen, furyl        (optionally substituted on carbon by 1 or 2 nitro groups),        thienyl (optionally substituted on carbon by 1 or 2 nitro        groups), morpholino, furyl(C₁₋₄)alkyl (wherein furyl is        optionally substituted on carbon by 1 or 2 nitro groups),        thienyl(C₁₋₄)alkyl (wherein thienyl is optionally substituted on        carbon by 1 or 2 nitro groups), phenyl (optionally substituted        by 1 or 2 groups selected from nitro, halo, cyano and hydroxy),        C₂₋₄alkenyl, cyano(C₁₋₄)alkyl, cyclo(C₃₋₈)alkyl,        amino(C₁₋₄)alkyl (optionally substituted on nitrogen by 1 or 2        groups selected from hydrogen, C₁₋₄alkyl, hydroxy,        hydroxy(C₁₋₄)alkyl, dihydroxy(C₁₋₄)alkyl, aryl and        aryl(C₁₋₄)alkyl) and C₁₋₄alkylS(O)_(c)(C₁₋₄)alkyl (wherein c is        0, 1 or 2).

In another aspect of the invention R¹⁴ is selected from hydrogen, halo,cyano, C₁₋₄alkoxy, C₁₋₄alkyl (optionally substituted by 1 or 2 hydroxygroups) and cyanoC₁₋₄alkyl.

In another aspect of the invention R¹⁴ is selected from hydrogen, —COR³,(R²)(R³)NCO—, and (R²)(R³)NSO₂—;

-   -   wherein R² is selected from hydrogen or C₁₋₄alkyl and R³ is        selected from hydrogen, methyl, hydroxyethyl, hydroxypropyl,        1,3-dihydroxyprop-2-yl, 3-hydroxy-2-hydroxymethylpropyl,        2,3-dihydroxypropyl, cyanomethyl, cyanoethyl, cyanopropyl,        cyanomethylcarbonyl, cyanoethylcarbonyl, cyanopropylcarbonyl,        carbamoyl, trifluoromethylcarbonyl, carboxymethanoyl,        4-amino-4-carboxybutanoyl, carboxyethyl, formyl, acetyl,        propanoyl, methanesulfinyl, methanesulfonyl,        morpholinomethylcarbonyl, phenylcarbonyl, furylcarbonyl,        thienylcarbonyl, nitrofurylcarbonyl, pyrazinylcarbonyl,        cyclopropylcarbonyl, morpholinocarbonyl, methylmercaptoethyl,        N,N-(methyl)₂carbamoyl, 4-methylpiperazinocarbonyl,        thienylsulfonyl, N-ethylcarbamoyl, N-allylcarbamoyl,        N-dinitrophenylcarbamoyl, pyridinylcarbonyl,        cyanophenylcarbonyl, hydroxyphenylcarbonyl, acryloyl,        2-amino-2-carboxyethylcarbonyl,        2-(tert-butoxycarbonyl)-2-(tert-butoxycarbonylamino)ethylcarbonyl,        2-(tert-butoxycarbonyl)ethylcarbonyl, aminobutanoyl,        aminopropanoyl, aminoacetyl, N-methylaminoacetyl,        3-amino-3-carboxypropanoyl, chloroacetyl, hydroxyacetyl,        N-methyl-N-hydroxyethylaminoacetyl,        N-benzyl-N-hydroxyethylaminoacetyl,        N-(2,3-dihydroxypropyl)-N-methylaminoacetyl,        hydroxypiperidinoaminoacetyl, hydroxypyrrolidinylaminoacetyl and        N,N-bis(hydroxyethyl)aminoacetyl.

In one aspect of the present invention m is 1 or 2.

In another aspect of the invention m is 1.

In one aspect of the present invention R⁴ is selected from hydrogen,halo, cyano, hydroxy, fluoromethyl, difluoromethyl and trifluoromethyl.

In another aspect of the invention R⁴ is hydrogen or halo.

Preferably R⁴ is selected from hydrogen, chloro or bromo.

More preferably R⁴ is chloro.

A preferred class of compound is of the formula (1) wherein;

-   -   n is 1 or 2;    -   R¹ is independently selected from hydrogen, halo, cyano, nitro,        hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl and        groups of the formula A or A′:        wherein x is 0 or 1, r is 0, 1, 2 or 3, s is 1 or 2 and u is 1        or 2; provided that the hydroxy group is not a substituent on        the ring carbon adjacent to the ring oxygen;    -   B is heterocyclyl;    -   R¹⁴ is selected from is selected from hydrogen, C₁₋₄alkyl        (optionally substituted by 1 or 2 hydroxy groups),        C₅₋₇cycloalkyl (optionally substituted with 1 or 2 hydroxy        groups), cyano(C₁₋₄)alkyl, -COR³, (R²)(R³)NCO—, and        (R²)(R³)NSO₂—;    -   R² and R³ are independently selected from C₁₋₄alkyl (substituted        by 1 or 2 hydroxy groups), C₅₋₇cycloalkyl (optionally        substituted with 1 or 2 hydroxy groups), cyano(C₁₋₄)alkyl,        fluoromethylcarbonyl, difluoromethylcarbonyl,        trifluoromethylcarbonyl, C₁₋₄alkyl (substituted by R⁸), —OR⁸ and        R⁸;    -   R⁸ is independently selected from hydrogen, furyl (optionally        substituted on carbon by 1 or 2 nitro groups), thienyl        (optionally substituted on carbon by 1 or 2 nitro groups),        morpholino, furyl(C₁₋₄)alkyl (wherein furyl is optionally        substituted on carbon by I or 2 nitro groups),        thienyl(C₁₋₄)alkyl (wherein thienyl is optionally substituted on        carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl,        imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl,        tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl,        morpholino, pyridyl, phenyl (optionally substituted by 1 or 2        groups selected from nitro, halo, cyano, hydroxy and C₁₋₄alkyl),        pyrazinyl, piperazinyl, 4-methylpiperazino, C₁₋₄alkyl,        C₂₋₄alkenyl, cyclo(C₃₋₈)alkyl, C₁₋₄alkoxy, cyano(C₁₋₄)alkyl,        amino(C₁₋₄)alkyl (optionally substituted on nitrogen by 1 or 2        groups selected from hydrogen, C₁₋₄alkyl, hydroxy,        hydroxy(C₁₋₄)alkyl, dihydroxy(C₁₋₄)alkyl, aryl and        aryl(C₁₋₄)alkyl), C₁₋₄alkylS(O)_(c)(C₁₋₄)alkyl (wherein c is 0,        1 or 2), —CH₂CH(CO₂R⁹)N(R⁹R¹⁰), —CH₂OR⁹, (R⁹)(R¹⁰)N—, —COOR⁹,        —CH₂COOR⁹, —CH₂CONR⁹R¹⁰, and —CH₂CH₂CH(WR⁹R¹⁰)CO₂R⁹;    -   R⁹ and R¹⁰ are independently selected from hydrogen, C₁₋₄alkyl        (optionally substituted by 1 or 2 hydroxy groups),        C₅₋₇cycloalkyl (optionally substituted by 1 or 2 hydroxy        groups), C₂₋₄alkenyl, cyano(C₁₋₄)alkyl, phenyl (optionally        substituted by 1 or 2 groups selected from nitro, halo, hydroxy        and cyano) and C₁₋₄alkyl substituted by R¹³; or    -   R⁹ and R¹⁰ can together with the nitrogen to which they are        attached form 4- to 6-membered ring where the ring is optionally        substituted on carbon by 1 or 2 substituents selected from oxo,        hydroxy, carboxy, halo, nitro, nitroso, cyano, isocyano, amino,        N—C₁₋₄alkylamino, NN—(C₁₋₄)₂alkylamino, carbonyl, C₁₋₄alkoxy,        heterocyclyl, C₁₋₄alkanoyl, and C₁₋₄alkylS(O)_(f)(C₁₋₄)alkyl        (wherein f is 0, 1 or 2);    -   R¹³ is selected from C₁₋₄alkoxy, furyl (optionally substituted        on carbon by 1 or 2 nitro groups), thienyl (optionally        substituted on carbon by 1 or 2 nitro groups), morpholino,        furyl(C₁₋₄)alkyl (wherein furyl is optionally substituted on        carbon by 1 or 2 nitro groups), thienyl(C₁₋₄)alkyl (wherein        thienyl is optionally substituted on carbon by 1 or 2 nitro        groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl,        pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl,        tetrahydrothiopyranyl, tetrahydrothienyl, phenyl (optionally        substituted by 1 or 2 groups selected from nitro, halo, cyano,        hydroxy and C₁₋₄alkyl), pyrazinyl, piperazinyl,        C₁₋₄alkylS(O)_(d)(C₁₋₄)alkyl (wherein d is 0, 1 or 2);    -   m is 1 or 2;    -   R⁴ is hydrogen or halo;    -   or a pharmaceutically acceptable salt or in-vivo hydrolysable        ester thereof.

Another preferred class of compound is of the formula (1) wherein:

-   -   n is 1 or 2;    -   R¹ is independently selected from hydrogen, halo, nitro,        hydroxy, C₁₋₄alkyl and groups of the formula A or A′:        wherein x is 0 or 1, r is 0, 1, 2 or 3, s is 1 or 2 and u is 1        or 2; provided that the hydroxy group is not a substituent on        the ring carbon adjacent to the ring oxygen;    -   B is heterocyclyl;    -   R¹⁴ is selected from is selected from hydrogen, C₁₋₄alkyl,        cyano(C₁₋₄)alkyl, —COR³, (R²)(R³)NCO—, and (R²)(R³)NSO₂—;    -   R² and R³ are independently selected from C₁₋₄alkyl (substituted        by 1 or 2 hydroxy groups), cyano(C₁₋₄)alkyl,        trifluoromethylcarbonyl, C₁₋₄alkyl (substituted by R⁸), —OR⁸ and        R⁸;    -   R⁸ is independently selected from hydrogen, furyl (optionally        substituted on carbon by 1 or 2 nitro groups), thienyl        (optionally substituted on carbon by 1 or 2 nitro groups),        morpholino, furyl(C₁₋₄)alkyl (wherein furyl is optionally        substituted on carbon by 1 or 2 nitro groups),        thienyl(C₁₋₄)alkyl (wherein thienyl is optionally substituted on        carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl,        imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl,        tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl,        phenyl (optionally substituted by 1 or 2 groups selected from        nitro, halo, cyano, hydroxy and C₁₋₄alkyl), pyrazinyl,        piperazinyl, 4-methylpiperazino, C₁₋₄alkyl, C₂₋₄alkenyl,        cyclo(C₃₋₈)alkyl, C₁₋₄alkoxy, cyano(C₁₋₄)alkyl, amino(C₁₋₄)alkyl        (optionally substituted on nitrogen by 1 or 2 groups selected        from hydrogen, C₁₋₄alkyl, hydroxy, hydroxy(C₁₋₄)alkyl,        dihydroxy(Cl 4)alkyl, aryl and aryl(C₁₋₄)alkyl),        C₁₋₄alkylS(O)_(c)(C₁₋₄)alkyl (wherein c is 0, 1 or 2),        —CH₂CH(CO₂R⁹)N(R⁹R¹⁰), —CH₂OR⁹, (R⁹)(R¹⁰)N—, —COOR⁹, —CH₂COOR⁹,        —CH₂CONR⁹R¹⁰, and —CH₂CH₂CH(NR⁹R¹⁰)CO₂R⁹;    -   R⁹ and R¹⁰ are independently selected from hydrogen, C₁₋₄alkyl        (optionally substituted by 1 or 2 hydroxy groups),        C₅₋₇cycloalkyl (optionally substituted by 1 or 2 hydroxy        groups), C₂₋₄alkenyl, cyano(C₁₋₄)alkyl and phenyl (optionally        substituted by 1 or 2 groups selected from nitro, halo, hydroxy        and cyano); or R⁹ and R¹⁰ can together with the nitrogen to        which they are attached form 4- to 6-membered ring where the        ring is optionally substituted on carbon by 1 or 2 substituents        selected from oxo, hydroxy, carboxy, halo, nitro, nitroso,        cyano, isocyano, amino, N—C₁₋₄alkylamino, NN—(C₁₋₄)₂alkylamino,        carbonyl, C₁₋₄alkoxy, heterocyclyl, C₁₋₄alkanoyl, and        C₁₋₄alkylS(O)_(f)(C₁₋₄)alkyl (wherein f is 0, 1 or 2);    -   m is 1 or 2;    -   R⁴ is hydrogen or halo;    -   or a pharmaceutically acceptable salt or in-vivo hydrolysable        ester thereof.

Another preferred class of compound is of the formula (1) wherein:

-   -   n is 1 or 2;    -   R¹ is independently selected from hydrogen, halo, nitro,        hydroxy, C₁₋₄alkyl and groups of the formula A or A′:        wherein x is 0 or 1, r is 0, 1, 2 or 3, s is 1 or 2 and u is 1        or 2; provided that the hydroxy group is not a substituent on        the ring carbon adjacent to the ring oxygen;    -   B is heterocyclyl;    -   R¹⁴ is selected from is selected from C₁₋₄alkyl,        cyano(C₁₋₄)alkyl, —COR³, (R²)(R³)NCO—, and (R²)(R³)NSO₂—;    -   R² and R³ are independently selected from C₁₋₄alkyl, C₁₋₄alkyl        (substituted by R⁸),    -   —OR⁸ and R⁸;    -   R⁸ is independently selected from hydrogen, furyl (optionally        substituted on carbon by 1 or 2 nitro groups), thienyl        (optionally substituted on carbon by 1 or 2 nitro groups),        morpholino, furyl(C₁₋₄)alkyl (wherein furyl is optionally        substituted on carbon by 1 or 2 nitro groups),        thienyl(C₁₋₄)alkyl (wherein thienyl is optionally substituted on        carbon by 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl,        imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl,        tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl,        phenyl (optionally substituted by 1 or 2 groups selected from        nitro, halo, cyano, hydroxy and C₁₋₄alkyl), pyrazinyl,        piperazinyl, C₁₋₄alkyl, C₂₋₄alkenyl, cyclo(C₃₋₈)alkyl,        C₁₋₄alkoxy, cyano(C₁₋₄)alkyl, amino(C₁₋₄)alkyl (optionally        substituted on nitrogen by 1 or 2 groups selected from hydrogen,        C₁₋₄alkyl, hydroxy, hydroxy(C₁₋₄)alkyl, dihydroxy(C]₄)alkyl,        aryl and aryl(C₁₋₄)alkyl), C₁₋₄alkylS(O)_(c)(C₁₋₄)alkyl (wherein        c is 0, 1 or 2), —CH₂CH(CO₂R⁹)N(R⁹R¹⁰), —CH₂OR⁹, (R⁹)(R¹⁰)N—,        —COOR⁹, —CH₂COOR⁹, —CH₂CONR⁹R¹⁰, and —CH₂CH₂CH(NR⁹R¹⁰)CO₂R⁹;    -   R⁹ and R¹⁰ are independently C₁₋₄alkenyl or phenyl (optionally        substituted by nitro, halo or cyano);    -   m is 1;    -   R⁴ is chloro;    -   or a pharmaceutically acceptable salt or in-vivo hydrolysable        ester thereof.

Another preferred class of compound is of the formula (1) wherein:

-   -   n is 1 or 2;    -   R¹ is independently selected from hydrogen, halo, nitro,        hydroxy, C₁₋₄alkyl and groups of the formula A or A′:    -   wherein x is 0 or 1, r is 0, 1, 2 or 3, s is 1 or 2 and u is 1        or 2; provided that the hydroxy group is not a substituent on        the ring carbon adjacent to the ring oxygen;    -   B is heterocyclyl;    -   R¹⁴ is selected from hydrogen, halo, cyano, C₁₋₄alkoxy,        C₁₋₄alkyl (optionally substituted by 1 or 2 hydroxy groups        provided that when there are 2 hydroxy groups they are not        substituents on the same carbon) and cyanoC₁₋₄alkyl;    -   m is 1;    -   R⁴ is chloro;    -   or a pharmaceutically acceptable salt or in-vivo hydrolysable        ester thereof.

Another preferred class of compound is of the formula (1) wherein:

-   -   n is 1 or 2;    -   R¹ is independently selected from hydrogen, halo, nitro,        hydroxy, C₁₋₄alkyl and RI is of the formula A or A′:        wherein x is 0 or 1, r is 0, 1, 2 or 3, s is 1 or 2 and u is 1        or 2; provided that the hydroxy group is not a substituent on        the ring carbon adjacent to the ring oxygen;    -   B is phenyl;    -   R¹⁴ is selected from is selected from C₁₋₄alkyl,        cyano(C₁₋₄)alkyl, —COR³, (R²)(R³)NCO—, and (R²)(R³)NSO₂—;    -   R² and R³ are independently selected from C₁₋₄alkyl, C₁₋₄alkyl        (substituted by R⁸), OR⁸ and R⁸;    -   R⁸ is independently selected from hydrogen, heterocyclyl        (optionally substituted on carbon or nitrogen by 1 or 2 groups        selected from nitro, halo, hydroxy, cyano and C₁₋₄alkyl),        (heterocyclyl)(C₁₋₄)alkyl (optionally substituted on carbon or        nitrogen by 1 or 2 groups selected from nitro, halo, hydroxy,        cyano and C₁₋₄alkyl), aryl (optionally substituted by 1 or 2        groups selected from nitro, halo, cyano, hydroxy and C₁₋₄alkyl),        C₁₋₄alkyl, C₂₋₄alkenyl, cyclo(C₃₋₈)alkyl, C₁₋₄alkoxy,        cyano(C₁₋₄)alkyl, amino(C₁₋₄)alkyl (optionally substituted on        nitrogen by I or 2 groups selected from hydrogen, C₁₋₄alkyl,        hydroxy, hydroxy(C₁₋₄)alkyl, dihydroxy(C₁₋₄)alkyl, aryl and        aryl(C₁₋₄)alkyl), C₁₋₄alkylS(O)_(c)(C₁₋₄)alkyl (wherein c is 0,        1 or 2), —(CH₂)_(u)CH(CO₂R⁹)N(R⁹R¹⁰) (wherein u is 0, 1 or 2),        —CH₂OR⁹, (R⁹)(R¹⁰)N—, and —CH₂COOR⁹, —CH₂CONR⁹R¹⁰,        —CH₂CH₂CH(NR⁹R¹)CO₂R⁹;    -   R⁹ and R¹⁰ are independently selected from hydrogen, C₁₋₄alkyl        (optionally substituted by 1 or 2 hydroxy groups),        C₅₋₇cycloalkyl (optionally substituted by 1 or 2 hydroxy        groups), C₂₋₄alkenyl, cyano(C₁₋₄)alkyl, and phenyl (optionally        substituted by 1 or 2 groups selected from nitro, halo, hydroxy        and cyano);    -   m is 1;    -   R⁴ is chloro;    -   or a pharmaceutically acceptable salt or in-vivo hydrolysable        ester thereof.

In another aspect of the invention, preferred compounds of the inventionare any one of:

-   -   methyl        (S)-5-{1-[(5-chloro-1H-indol-2-ylcarbonyl)amino]-2-phenylethyl}oxazole-4-carboxylate;    -   or a pharmaceutically acceptable salt or an in vivo hydrolysable        ester thereof.

Another aspect of the present invention provides a process for preparinga compound of formula (1) or a pharmaceutically acceptable salt or an invivo hydrolysable ester thereof which process (wherein B, R¹, R⁴, R¹⁴ mand n are, unless otherwise specified, as defined in formula (1))comprises of:

-   -   a) reacting an acid of the formula (2):        or an activated derivative thereof, with an amine of formula        (3):        and thereafter if necessary:    -   i) converting a compound of the formula (1) into another        compound of the formula (1);    -   ii) removing any protecting groups;    -   iii) forming a pharmaceutically acceptable salt or in vivo        hydrolysable ester.

Specific reaction conditions for the above reaction are as follows.

Process a) Acids of formula (2) and amines of formula (3) may be coupledtogether in the presence of a suitable coupling reagent. Standardpeptide coupling reagents known in the art can be employed as suitablecoupling reagents, or for example carbonyldiimidazole,1-ethyl-3-(3-dimethylaminopropyl)carbodi-imide hydrochloride anddicyclohexyl-carbodiimide, optionally in the presence of a catalyst suchas 1-hydroxybenzotriazole, dimethylaminopyridine or4-pyrrolidinopyridine, optionally in the presence of a base for exampletriethylamine, di-isopropylethylamine, pyridine, or 2,6-dialkylpyridinessuch as 2,6-lutidine or 2,6-di-tert-butylpyridine. Suitable solventsinclude dimethylacetamide, dichloromethane, benzene, tetrahydrofuran anddimethylformamide. The coupling reaction may conveniently be performedat a temperature in the range of −40 to 40° C.

Suitable activated acid derivatives include acid halides, for exampleacid chlorides, and active esters, for example pentafluorophenyl esters.The reaction of these types of compounds with amines is well known inthe art, for example they may be reacted in the presence of a base, suchas those described above, and in a suitable solvent, such as thosedescribed above. The reaction may conveniently be performed at atemperature in the range of 40 to 40° C.

The acids of formula (2) are commercially available or they are knowncompounds or they are prepared by processes known in the art.

Processes for the preparation of compounds of formula (3) often involveheterocyclic ring formation. Compounds of formula (3) may therefore beprepared by processes known in the art and in particular with referenceto Alan R. Katritzky, Comprehensive Heterocyclic Chemistry, PergamonPress. Processes for the preparation of compounds of formua (3) may alsobe found in Tett. Letts., Vol23, no2, p 235.

It will be appreciated that certain of the various ring substituents inthe compounds of the present invention may be introduced by standardaromatic substitution reactions or generated by conventional functionalgroup modifications either prior to or immediately following theprocesses mentioned above, and as such are included in the processaspect of the invention. Such reactions and modifications include, forexample, introduction of a substituent by means of an aromaticsubstitution reaction, reduction of substituents, alkylation ofsubstituents and oxidation of substituents. The reagents and reactionconditions for such procedures are well known in the chemical art.Particular examples of aromatic substitution reactions include theintroduction of a nitro group using concentrated nitric acid, theintroduction of an acyl group using, for example, an acyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; and the introduction of a halogen group. Particular examplesof modifications include the reduction of a nitro group to an aminogroup by for example, catalytic hydrogenation with a nickel catalyst ortreatment with iron in the presence of hydrochloric acid with heating;oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups inthe compounds. The instances where protection is necessary or desirableand suitable methods for protection are known to those skilled in theart. Conventional protecting groups may be used in accordance withstandard practice (for illustration see T. W. Green, Protective Groupsin Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactantsinclude groups such as amino, carboxy or hydroxy it may be desirable toprotect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group mayberemoved, for example, by treatment with a suitable acid ashydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid andan arylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

Certain intermediates in the preparation of a compound of the formula(1) are novel and form another aspect of the invention.

As stated hereinbefore the compounds defined in the present inventionpossesses glycogen phosphorylase inhibitory activity. This property maybe assessed, for example, using the procedure set out below.

Assay

The activity of the compounds is determined by measuring the inhibitoryeffect of the compounds in the direction of glycogen synthesis, theconversion of glucose-I-phosphate into glycogen with the release ofinorganic phosphate, as described in EP 0 846 464 A2. The reactions werein 96 well microplate format in a volume of 100μt. The change in opticaldensity due to inorganic phosphate formation was measured at 620 nM in aLabsystems iEMS Reader MF by the general method of (Nordlie R. C andArion W. J, Methods of Enzymology, 1966, 619-625). The reaction is in 50mM HEPES (N-(2-Hydroxyethyl)piperazine-N′-(2-ethanesulfonicacid);4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid), 2.5mM MgCl₂,2.25mM ethylene glycol-bis(b-aminoethyl ether) N,N,N′,N′-tetraaceticacid, 100 mM KCl, 2 mM D-(+)-glucose pH7.2, containing 0.5 mMdithiothreitol, the assay buffer solution, with 0.1 mg type IIIglycogen, 0.15 ug glycogen phosphorylase a (GPa) from rabbit muscle and0.5 mM glucose-1-phosphate. GPa is pre-incubated in the assay buffersolution with the type III glycogen at 2.5 mg ml⁻¹ for 30 minutes. 40μlof the enzyme solution is added to 25 μl assay buffer solution and thereaction started with the addition of 25μl 2 mM glucose-1-phosphate.Compounds to be tested are prepared in 10 μl 10% DMSO in assay buffersolution, with final concentration of 1% DMSO in the assay. Thenon-inhibited activity of GPa is measured in the presence of 10 μl 10%DMSO in assay buffer solution and maximum inhibition measured in thepresence of 30 μM CP320626 (Hoover et al (1998) J Med Chem 41,2934-8;Martin et al (1998) PNAS 95, 1776-81). The reaction is stopped after 30min with the addition of 50 μl acidic ammonium molybdate solution, 12ugml⁻¹ in 3.48% H₂SO₄ with 1% sodium lauryl sulphate and 10 ug ml⁻¹ascorbic acid. After 30 minutes at room temperature the absorbency at620 nm is measured.

The assay is performed at a test concentration of inhibitor of 10 μM or100 μM. Compounds demonstrating significant inhibition at one or both ofthese concentrations may be further evaluated using a range of testconcentrations of inhibitor to determine an IC₅₀, a concentrationpredicted to inhibit the enzyme reaction by 50%.

Activity is calculated as follows:% inhibition=(1−(compound OD620−fully inhibited OD620)/(non-inhibitedrate OD620−fully inhibited OD620))*100.

-   -   OD620=optical density at 620nM.

Typical IC₅₀ values for compounds of the invention when tested in theabove assay are in the range 100 μM to 1 nM.

The activity of the compounds is alternatively determined by measuringthe inhibitory effect of the compounds on glycogen degradation, theproduction of glucose-1-phosphate from glycogen is monitored by themultienzyme coupled assay, as described in EP 0 846 464 A2, generalmethod of Pesce et al ( Pesce, M A, Bodourian, S H, Harris, R C, andNicholson, J F (1977) Clinical Chemistry 23, 1171-1717). The reactionswere in 384 well microplate format in a volume of 50 μl. The change influorescence due to the conversion of the co-factor NAD to NADH ismeasured at 340 nM excitation, 465 nm emission in a Tecan UltraMultifunctional Microplate Reader. The reaction is in 5OmM HEPES, 3.5 mMKH₂PO₄, 2.5 mM MgCl₂, 2.5 mM ethylene glycol-bis(b-aminoethyl ether)N,N,N′,N′-tetraacetic acid, 100 mM KCl, 8 mM D-(+)-glucose pH7.2,containing 0.5 mM dithiothreitol, the assay buffer solution. Humanrecombinant liver glycogen phosphorylase a (hrl GPa) 20 nM ispre-incubated in assay buffer solution with 6.25 mM NAD, 1.25 mg typeIII glycogen at 1.25 mg ml⁻¹ the reagent buffer, for 30 minutes. Thecoupling enzymes, phosphoglucomutase and glucose-6-phosphatedehydrogenase (Sigma) are prepared in reagent buffer, finalconcentration 0.25 Units per well. 20 μl of the hrl GPa solution isadded to 10 μl compound solution and the reaction started with theaddition of 20 ul coupling enzyme solution. Compounds to be tested areprepared in 10 μl 5% DMSO in assay buffer solution, with finalconcentration of 1% DMSO in the assay. The non-inhibited activity of GPais measured in the presence of 10 μl 5% DMSO in assay buffer solutionand maximum inhibition measured in the presence of 5 mgs ml⁻¹N-ethylmaleimide. After 6 hours at 30° C. Relative Fluoresence Units(RFUs) are measured at 340 nM excitation, 465 nm emission.

The assay is performed at a test concentration of inhibitor of 10 μM or100 μM. Compounds demonstrating significant inhibition at one or both ofthese concentrations may be further evaluated using a range of testconcentrations of inhibitor to determine an IC₅₀, a concentrationpredicted to inhibit the enzyme reaction by 50%.

Activity is calculated as follows:% inhibition=(1−(compound RFUs−fully inhibited RFUs)/(non-inhibited rateRFUs−fully inhibited RFUs))*100.

Typical IC₅₀ values for compounds of the invention when tested in theabove assay are in the range 100 μM to 1 nM. For example, Example 1 gavean IC₅₀ value of 2.4 μM.

The inhibitory activity of compounds was further tested in rat primaryhepatocytes.

Rat hepatocytes were isolated by the collagenase perfusion technique,general method of Seglen (P. O. Seglen, Methods Cell Biology (1976) 1329-83). Cells were cultured on Nunclon six well culture plates in DMEMwith high level of glucose containing 10% foetal calf serum, NEAA,Glutamine, penicillin /streptomycin ((100 units/100 ug)/ml) for 4 to 6hours. The hepatocytes were then cultured in the DMEM solution withoutfoetal calf serum and with 10 nM insulin and 10 nM dexamethasone.Experiments were initiated after 18-20 hours culture by washing thecells and adding Krebs-Henseleit bicarbonate buffer containing 2.5mMCaCl₂ and 1% gelatin. The test compound was added and 5 minutes laterthe cells were challenged with 25 nM glucagon. The Krebs-Henseleitsolution was removed after 60 min incubation at 37° C., 95% O₂/5% CO₂and the glucose concentration of the Krebs-Henseleit solution measured.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the formula(1), or a pharmaceutically acceptable salt or in vivo hydrolysable esterthereof, as defined hereinbefore in association with apharmaceutically-acceptable diluent or carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art;

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),colouring agents, flavouring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Compositions for administration by inhalation may be in the form of aconventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient. For furtherinformation on Routes of Administration and Dosage Regimes the reader isreferred to Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990.

The compound of formula (1) will normally be administered to awarm-blooded animal at a unit dose within the range 5-5000 mg per squaremeter body area of the animal, i.e. approximately 0. 1-100 mg/kg, andthis normally provides a therapeutically-effective dose. A unit doseform such as a tablet or capsule will usually contain, for example 1-250mg of active ingredient. Preferably a daily dose in the range of 1-50mg/kg is employed. However the daily dose will necessarily be varieddepending upon the host treated, the particular route of administration,and the severity of the illness being treated. Accordingly the optimumdosage may be determined by the practitioner who is treating anyparticular patient.

The inhibition of glycogen phosphorylase activity described herein maybe applied as a sole therapy or may involve, in addition to the subjectof the present invention, one or more other substances and/ortreatments. Such conjoint treatment may be achieved by way of thesimultaneous, sequential or separate administration of the individualcomponents of the treatment. Simultaneous treatment may be in a singletablet or in separate tablets. For example in the treatment of diabetesmellitus chemotherapy may include the following main categories oftreatment:

-   -   1) Insulin and insulin analogues;    -   2) Insulin secretagogues including sulphonylureas (for example        glibenclamide, glipizide) and prandial glucose regulators (for        example repaglinide, nateglinide);    -   3) Insulin sensitising agents including PPARg agonists (for        example pioglitazone and rosiglitazone);    -   4) Agents that suppress hepatic glucose output (for example        metformin).    -   5) Agents designed to reduce the absorption of glucose from the        intestine (for example acarbose);    -   6) Agents designed to treat the complications of prolonged        hyperglycaemia;    -   7) Anti-obesity agents (for example sibutramine and orlistat);    -   8) Anti- dyslipidaemia agents such as, HMG-CoA reductase        inhibitors (statins, eg pravastatin); PPARoc agonists (fibrates,        eg gemfibrozil); bile acid sequestrants (cholestyramine);        cholesterol absorption inhibitors (plant stanols, synthetic        inhibitors); bile acid absorption inhibitors (IBATi) and        nicotinic acid and analogues (niacin and slow release        formulations);    -   9) Antihypertensive agents such as, P blockers (eg atenolol,        inderal); ACE inhibitors (eg lisinopril); Calcium antagonists        (eg. nifedipine); Angiotensin receptor antagonists (eg        candesartan), oc antagonists and diuretic agents (eg.        furosemide, benzthiazide);    -   10) Haemostasis modulators such as, antithrombotics, activators        of fibrinolysis and antiplatelet agents; thrombin antagonists;        factor Xa inhibitors; factor VIIa inhibitors); antiplatelet        agents (eg. aspirin, clopidogrel); anticoagulants (heparin and        Low molecular weight analogues, hirudin) and warfarin; and    -   11) Anti-inflammatory agents, such as non-steroidal        anti-inflammatory drugs (eg. aspirin) and steroidal        anti-inflammatory agents (eg. cortisone).

According to a further aspect of the present invention there is provideda compound of the formula (1), or a pharmaceutically acceptable salt orin vivo hydrolysable ester thereof, as defined hereinbefore, for use ina method of treatment of a warm-blooded animal such as man by therapy.

According to an additional aspect of the invention there is provided acompound of the formula (1), or a pharmaceutically acceptable salt or invivo hydrolysable ester thereof, as defined hereinbefore, for use as amedicament.

According to an additional aspect of the invention there is provided acompound of the formula (1), or a pharmaceutically acceptable salt or invivo hydrolysable ester thereof, as defined hereinbefore, for use as amedicament in the treatment of type 2 diabetes, insulin resistance,syndrome X, hyperinsulinaemia, hyperglucagonaemia, cardiac ischaemia orobesity in a warm-blooded animal such as man.

According to this another aspect of the invention there is provided theuse of a compound of the formula (1), or a pharmaceutically acceptablesalt or in vivo hydrolysable ester thereof, as defined hereinbefore inthe manufacture of a medicament for use in the treatment of type 2diabetes, insulin resistance, syndrome X, hyperinsulinaemia,hyperglucagonaemia, cardiac ischaemia or obesity in a warm-bloodedanimal such as man.

According to this another aspect of the invention there is provided theuse of a compound of the formula (1), or a pharmaceutically acceptablesalt or in vivo hydrolysable ester thereof, as defined hereinbefore inthe manufacture of a medicament for use in the treatment of type 2diabetes in a warm-blooded animal such as man.

According to a further feature of this aspect of the invention there isprovided a method of producing a glycogen phosphorylase inhibitoryeffect in a warm-blooded animal, such as man, in need of such treatmentwhich comprises administering to said animal an effective amount of acompound of formula (1).

According to this further feature of this aspect of the invention thereis provided a method of treating type 2 diabetes, insulin resistance,syndrome X, hyperinsulinaemia, hyperglucagonaemia, cardiac ischaemia orobesity in a warm-blooded animal, such as man, in need of such treatmentwhich comprises administering to said animal an effective amount of acompound of formula (1).

According to this further feature of this aspect of the invention thereis provided a method of treating type 2 diabetes in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula (1).

As stated above the size of the dose required for the therapeutic orprophylactic treatment of a particular cell-proliferation disease willnecessarily be varied depending on the host treated, the route ofadministration and the severity of the illness being treated. A unitdose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg isenvisaged.

In addition to their use in therapeutic medicine, the compounds offormula (1) and their pharmaceutically acceptable salts are also usefulas pharmacological tools in the development and standardisation of invitro and in vivo test systems for the evaluation of the effects ofinhibitors of cell cycle activity in laboratory animals such as cats,dogs, rabbits, monkeys, rats and mice, as part of the search for newtherapeutic agents.

In the above other pharmaceutical composition, process, method, use andmedicament manufacture features, the alternative and preferredembodiments of the compounds of the invention described herein alsoapply.

EXAMPLES

The invention will now be illustrated by the following non-limitingexamples in which, unless stated otherwise:

-   -   (i) temperatures are given in degrees Celsius (° C.); operations        were carried out at room or ambient temperature, that is, at a        temperature in the range of 18-25° C. and under an atmosphere of        an inert gas such as argon;    -   (ii) organic solutions were dried over anhydrous magnesium        sulphate; evaporation of solvent was carried out using a rotary        evaporator under reduced pressure (600-4000 Pascals; 4.5-30        mmHg) with a bath temperature of up to 60° C.;    -   (iii) in general, the course of reactions was followed by TLC        and reaction times are given for illustration only;    -   (iv) yields are given for illustration only and are not        necessarily those which can be obtained by diligent process        development; preparations were repeated if more material was        required;    -   (v) where given, NMR data is in the form of delta values for        major diagnostic protons, given in parts per million (ppm)        relative to tetramethylsilane (TMS) as an internal standard,        determined at 300 MHz using perdeuterio dimethyl sulphoxide        (DMSO-δ₆) as solvent unless otherwise indicated, other solvents        (where indicated in the text) include deuterated chloroform        CDCl₃;    -   (vi) chemical symbols have their usual meanings; SI units and        symbols are used;    -   (vii) solvent ratios are given in volume : volume (v/v) terms;

(viii) The following abbreviations are used: EtOAc ethyl acetate; DCMdichloromethane; HOBT 1-hydroxybenzotriazole; DIPEAdi-isopropylethylamine; EDAC1-ethyl-3-(3-dimethylaminopropyl)carbodi-imide hydrochloride;

Example 1 Methyl(S)-5-{1-[(5-chloro-1H-indol-2-ylcarbonyl)amino]-2-phenylethyl}oxazole-4-carboxylate

2-Carboxy-5-chloro-indole (146 mg, 0.75 mmol) was dissolved in DCM (5ml) containing HOBT (126 mg, 0.93 mmol), DIPEA (290 mg, 2.25 mmol) andmethyl (s)-5-(1-amino-2-phenylethyl)oxazole-4-carboxylatetrifluoroacetate (Method 1; 360 mg, 0.75 mmol). EDAC (178 mg, 0.93 mmol)was added and the mixture stirred at ambient temperature for 4 hours.The reaction mixture was diluted with ethyl acetate (30 ml), washed withdilute citric acid, water and brine, dried over magnesium sulphate andconcentrated. The crude material was purified by trituration withdiethyl ether to give the title compound as a white solid. (227mg, 65%)

NMR 3.1-3.2(1H,m); 3.25-3.3(1H,m); 3.8(3H,s); 5.9-6.0(1H,m);7.1-7.3(7H,m); 7.4(1H,d); 7.75(1H,d); 8.46(1H,s); 9.1(1H,d);11.68(1H,bs)

Method 1

Methyl (S)-5-(1-amino-2-phenylethyl)oxazole-4-carboxylatetrifluoroacetate

Methyl(S)-5-[1-(tert-butoxycarbonylamino)2-phenylethyl]oxazole-4-carboxylate,(Tett. Lett., 1982, 23, 235; 417mg) was dissolved in trifluoroaceticacid (3ml) and stood at ambient temperature for 1 hour and concentratedto give an oil. Trituration with diethyl ether gave the title compoundas a white solid. (281 mg).

NMR 3.1-3.25(1H,m); 3.3-3.4(1H,m); 3.7(3H,s); 5.2-5.3(1H,m); 7.05(2H,d);7.2-7.3(3H,m); 8.7(1H,s); 8.75-8.85(3H,bs)

1. A compound of formula (1):

wherein: n is 0, 1, or 2; m is 0, 1, or 2; R¹ is independently selectedfrom hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,N—C₁₋₄alkylcarbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, sulphamoyl,N—C₁₋₄alylsulphamoyl, N,N—(C₁₋₄alkyl)₂sulphamoyl, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy,N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, hydroxyC₁₋₄alkyl,fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, andgroups of the formula A or A′:

wherein x is 0 or 1, r is 0, 1, 2, or 3, s is 1 or 2 and u is 1 or 2;provided that the hydroxy group is not a substituent on the ring carbonadjacent to the ring oxygen; R⁴ is independently selected from hydrogen,halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl,trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, and C₁₋₄alkanoyl; B is phenyl orheterocyclyl; R¹⁴ is selected from hydrogen, halo, C₁₋₄alkyl (optionallysubstituted with 1 or 2 hydroxy groups), C₅₋₇cycloalkyl (optionallysubstituted with 1 or 2 hydroxy groups), C₁₋₄alkoxy, cyano,cyano(C₁₋₄)alkyl, —COR³, (R²)(R³)NCO—, and (R²)(R³)NSO₂—; R² and R³ areindependently selected from C₅₋₇cycloalkyl (optionally substituted with1 or 2 hydroxy groups), cyano(C₁₋₄)alkyl, 5- and 6-membered cyclicacetals and mono- and di-methyl derivatives thereof,tetrahydrothiopyranyl, 1-oxotetrahydrothiopyranyl,1,1-dioxotetrahydrothiopyranyl, fluoromethylcarbonyl,difluoromethylcarbonyl, trifluoromethylcarbonyl, C₁₋₄alkyl (optionallysubstituted with 1 or 2 R⁸ groups), —OR⁸, and R⁸; R⁸ is independentlyselected from hydrogen, 2,2-dimethyl-1,3-dioxolan-4-yl, heterocyclyl(optionally substituted on ring carbon or ring nitrogen with 1 or 2groups selected from hydrogen, nitro, halo, cyano, hydroxy, andC₁₋₄alkyl), (heterocyclyl)C₁₋₄alkyl (wherein the heterocyclyl isoptionally substituted on ring carbon or ring nitrogen with 1 or 2groups selected from hydrogen, nitro, halo, cyano, hydroxy, andC₁₋₄alkyl), aryl (optionally substituted with 1 or 2 groups selectedfrom nitro, halo, cyano, hydroxy, and C₁₋₄alkyl), C₁₋₄alkyl,C₂₋₄alkenyl, cyclo(C₃₋₈)alkyl, C₁₋₄alkoxy, cyano(C₁₋₄)alkyl,amino(C₁₋₄)alkyl (optionally substituted on nitrogen with 1 or 2 groupsselected from hydrogen, C₁₋₄alkyl, hydroxy, hydroxy(C₁₋₄)alkyl,dihydroxy(C₁₋₄)alkyl, aryl and aryl(C₁₋₄)alkyl),C₁₋₄alkylS(O)_(c)(C₁₋₄)alkyl (wherein c is 0, 1 or 2), —N(OH)CHO,—CH₂CH(CO₂R⁹)N(R⁹R¹⁰), —CH₂OR⁹, (R⁹)(R¹⁰)N—, —COOR⁹, —CH₂COOR⁹,—CH₂CONR⁹R¹⁰, and CH₂)_(u)CH(NR⁹R¹⁰)CO₂R⁹ (wherein u is 1, 2, or 3); R⁹and R¹⁰ are independently selected from hydrogen, hydroxy, C₁₋₄alkyl(optionally substituted with 1 or 2 hydroxy groups), C₅₋₇cycloalkyl(optionally substituted with 1 or 2 hydroxy groups), C₂₋₄alkenyl,cyano(C₁₋₄)alkyl, tetrahydrothiopyranyl, 1-oxotetrahydrothiopyranyl,1,1-dioxotetrahydrothiopyranyl, 2,2-dimethyl-1,3-dioxolan-4-yl, aryl(optionally substituted with 1 or 2 substituents selected from hydrogen,nitro, halo, hydroxy, and C₁₋₄alkyl), and C₁₋₄alkyl substituted withR¹³; or R⁹ and R¹⁰ together with the nitrogen to which they are attachedform a 4- to 6-membered ring where the ring is optionally substituted oncarbon with 1 or 2 substituents selected from oxo, hydroxy, carboxy,halo, nitro, nitroso, cyano, isocyano, amino, N—C 4alkylamino, N,N—(C₁₄alkyl)₂amino, carbonyl, C₁₋₄alkoxy, heterocyclyl, C₁₋₄alkanoyl,C₁₋₄alkylS(O)_(f)(C₁₋₄)alkyl (wherein f is 0, 1, or 2), —N(OH)CHO,(R¹¹)(R¹²)NCO—, (R¹¹)(R¹²)NSO₂—, —COCH₂OR¹¹, and (R¹¹)(R¹²)N—; R¹³ isselected from hydroxy, C₁₋₄alkoxy, heterocyclyl, C₁₋₄alkanoyl,C₁₋₄alkylS(O)_(d) (wherein d is 0, 1, or 2), —N(OH)CHO,—C(O)N(R¹¹)(R¹²), (R¹¹)(R¹²)NSO₂—, —COCH₂OR¹¹, and (R¹¹)(R¹²)N—; and R¹¹and R¹² are independently selected from hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy,hydroxyC₁₋₄alkyl, and C₁₋₄alkylS(O)_(e) (wherein e is 0, 1, or 2); or apharmaceutically acceptable salt or prodrug thereof.
 2. A compound ofclaim 1, wherein n is 1 or 2; R¹ is independently selected fromhydrogen, halo, cyano, nitro, hydroxy, fluoromethyl, difluoromethyl,trifluoromethyl, and groups of the formula A or A′:

wherein x is 0 or 1, r is 0, 1, 2, or 3, s is 1 or 2 and u is 1 or 2;provided that the hydroxy group is not a substituent on the ring carbonadjacent to the ring oxygen; B is heterocyclyl; R¹⁴ is selected from isselected from hydrogen, C₁₋₄alkyl (optionally substituted with 1 or 2hydroxy groups), C₅₋₇cycloalkyl (optionally substituted with 1 or 2hydroxy groups), cyano(C₁₋₄)alkyl, —COR³, (R²)(R³)NCO—, and(R²)(R³)NSO₂—; R² and R³ are independently selected from C₁₋₄alkyl(substituted with 1 or 2 hydroxy groups), C₅₋₇cycloalkyl (optionallysubstituted with 1 or 2 hydroxy groups), cyano(C₁₋₄)alkyl,fluoromethylcarbonyl, difluoromethylcarbonyl, trifluoromethylcarbonyl,C₁₋₄alkyl (substituted with R⁸), —OR⁸, and R⁸; R⁸ is independentlyselected from hydrogen, furyl (optionally substituted on carbon with 1or 2 nitro groups), thienyl (optionally substituted on carbon with 1 or2 nitro groups), morpholino, frryl(C₁₋₄)alkyl (wherein furyl isoptionally substituted on carbon with 1 or 2 nitro groups),thienyl(C₁₋₄)alkyl (wherein thienyl is optionally substituted on carbonwith 1 or 2 nitro groups), 1,2,4-oxadiazolyl, tetrazolyl, imidazolyl,pyrrolidinyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl,tetrahydrothiopyranyl, tetrahydrothienyl, morpholino, pyridyl, phenyl(optionally substituted with 1 or 2 groups selected from nitro, halo,cyano, hydroxy, and C₁₋₄alkyl), pyrazinyl, piperazinyl,4-methylpiperazino, C₁₋₄alkyl, C₂₋₄alkenyl, cyclo(C₃₋ ₈)alkyl,C₁₋₄alkoxy, cyano(C₁₋₄)alkyl, amino(C₁₋₄)alkyl (optionally substitutedon nitrogen with 1 or 2 groups selected from hydrogen, C₁₋₄alkyl,hydroxy, hydroxy(C₁₋₄)alkyl, dihydroxy(C₁₋₄)alkyl, aryl, andaryl(C₁₋₄)alkyl), C₁₋₄alkylS(O)_(c)(C₁₋₄)alkyl (wherein c is 0, 1, or2), —CH₂CH(CO₂R⁹)N(R⁹R¹⁰), —CH₂OR⁹, (R⁹)(R¹⁰)N—, —COOR⁹, —CH₂COOR⁹,—CH₂CONR⁹R¹⁰, and —CH₂CH₂CH(NR⁹R¹⁰)CO₂R⁹; R⁹ and R¹⁰ are independentlyselected from hydrogen, C₁₋₄alkyl (optionally substituted with 1 or 2hydroxy groups), C₅₋₇cycloalkyl (optionally substituted with 1 or 2hydroxy groups), C₂₋₄alkenyl, cyano(C₁₋₄)alkyl, phenyl (optionallysubstituted with 1 or 2 groups selected from nitro, halo, hydroxy, andcyano), and C₁₋₄alkyl substituted with R¹³; or R⁹ and R¹⁰ together withthe nitrogen to which they are attached form 4- to 6-membered ring wherethe ring is optionally substituted on carbon with 1 or 2 substituentsselected from oxo, hydroxy, carboxy, halo, nitro, nitroso, cyano,isocyano, amino, N—C₁₋₄alkylamino, N,N—(C₁₋₄)₂alkylamino, carbonyl,C₁₋₄alkoxy, heterocyclyl, C₁₋₄alkanoyl, and C₁₋₄alkylS(O)_(f)(C₁₋₄)alkyl(wherein f is 0, 1, or 2); R¹³ is selected from C₁₋₄alkoxy, furyl(optionally substituted on carbon with 1 or 2 nitro groups), thienyl(optionally substituted on carbon with 1 or 2 nitro groups), morpholino,furyl(C₁₋₄)alkyl (wherein furyl is optionally substituted on carbon with1 or 2 nitro groups), thienyl(C₁₋₄)alkyl (wherein thienyl is optionallysubstituted on carbon with 1 or 2 nitro groups), 1,2,4-oxadiazolyl,tetrazolyl, imidazolyl, pyrrolidinyl, piperidyl, tetrahydrofuryl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl, phenyl(optionally substituted with 1 or 2 groups selected from nitro, halo,cyano, hydroxy, and C₁₋₄alkyl), pyrazinyl, piperazinyl, andC₁₋₄alkylS(O)_(d)(C₁₋₄)alkyl (wherein d is 0, 1, or 2); m is 1 or 2; andR⁴ is hydrogen or halo; or a pharmaceutically acceptable salt or in-vivohydrolysable ester thereof.
 3. A compound of claim 1, wherein: n is 1 or2; R¹ is independently selected from hydrogen, halo, nitro, hydroxy,C₁₋₄alkyl, and groups of the formula A or A′

wherein x is 0 or 1, r is 0, 1, 2, or 3, s is 1 or 2 and u is 1 or 2;provided that the hydroxy group is not a substituent on the ring carbonadjacent to the ring oxygen; B is heterocyclyl; R¹⁴ is selected fromhydrogen, halo, cyano, C₁₋₄alkoxy, C₁₋₄alkyl (optionally substitutedwith 1 or 2 hydroxy groups, provided that when there are 2 hydroxygroups they are not substituents on the same carbon), andcyanoC₁₋₄alkyl; m is 1; and R⁴ is chloro; or a pharmaceuticallyacceptable salt or in-vivo hydrolysable ester thereof
 4. A compound ofclaim 1 wherein: n is 1 or 2; R¹ is independently selected fromhydrogen, halo, nitro, hydroxy, C₁₋₄alkyl, or R¹ is of the formula A orA′:

wherein x is 0 or 1, r is 0, 1, 2, or 3, s is 1 or 2 and u is 1 or 2;provided that the hydroxy group is not a substituent on the ring carbonadjacent to the ring oxygen; B is phenyl; R¹⁴ is selected fromC₁₋₄alkyl, cyano(C₁₋₄)alkyl, —COR³, (R²)(R³)NCO—, and (R²)(R³)NSO₂—; R²and R³ are independently selected from C₁₋₄alkyl, C₁₋₄alkyl (substitutedwith R⁸), OR⁸, and R⁸; R⁸ is independently selected from hydrogen,heterocyclyl (optionally substituted on carbon or nitrogen with 1 or 2groups selected from nitro, halo, hydroxy, cyano, and C₁₋₄alkyl),(heterocyclyl)(C₁₋₄)alkyl (optionally substituted on carbon or nitrogenwith 1 or 2 groups selected from nitro, halo, hydroxy, cyano, andC₁₋₄alkyl), aryl (optionally substituted with 1 or 2 groups selectedfrom nitro, halo, cyano, hydroxy, and C₁₋₄alkyl), C₁₋₄alkyl,C₂₋₄alkenyl, cyclo(C₃₋₈)alkyl, C₁₋₄alkoxy, cyano(C₁₋₄)alkyl,amino(C₁₋₄)alkyl (optionally substituted on nitrogen with 1 or 2 groupsselected from hydrogen, C₁₋₄alkyl, hydroxy, hydroxy(C₁₋₄)alkyl,dihydroxy(C₁₋₄)alkyl, aryl, and aryl(C₁₋₄)alkyl),C₁₋₄alkylS(O)_(c)(C₁₋₄)alkyl (wherein c is 0, 1, or 2),—(CH₂)_(u)CH(CO₂R⁹)N(R⁹R¹⁰) (wherein u is 0, 1, or 2), —CH₂OR⁹,(R⁹)(R¹⁰)N—, —COOR⁹, —CH₂COOR⁹, —CH₂CONR⁹R¹⁰, and—CH₂CH₂CH(NR⁹R¹⁰)CO₂R⁹; R⁹ and R¹⁰ are independently selected fromhydrogen, C₁₋₄alkyl (optionally substituted with 1 or 2 hydroxy groups),C₅₋₇cycloalkyl (optionally substituted with 1 or 2 hydroxy groups),C₂₋₅alkenyl, cyano(C₁₋₄)alkyl, and phenyl (optionally substituted with 1or 2 groups selected from nitro, halo, hydroxy, and cyano); m is 1; R⁴is chloro; or a pharmaceutically acceptable salt or in-vivo hydrolysableester thereof.
 5. A compound of claim 1 which is: methyl(S)-5-{1-[(5-chloro-1H-indol-2-ylcarbonyl)amino]-2-phenylethyl}oxazole-4-carboxylate;or a pharmaceutically acceptable salt or an in-vivo hydrolysable esterthereof.
 6. A pharmaceutical composition which comprises a compound ofclaim 1, or a pharmaceutically acceptable salt or in-vivo hydrolysableester thereof in association with a pharmaceutically acceptable diluentor carrier.
 7. A method for the treatment of type 2 diabetes, insulinresistance, syndrome X, hyperinsulinaemia, hyperglucagonaemia, cardiacischaemia or obesity in a warm-blooded animal, comprising administeringa compound of claim 1, or a pharmaceutically acceptable salt or in-vivohydrolysable ester thereof.
 8. A method for the treatment of type 2diabetes in a warm-blooded animal, comprising administering a compoundof claim 1, or a pharmaceutically acceptable salt or in-vivohydrolysable ester thereof.
 9. A process for the preparation of claim 1,which process comprises: reacting an acid of the formula (2)

or an activated derivative thereof; with an amine of formula (3)

and thereafter if necessary i) converting a compound of the formula (1)into another compound of the formula (1); ii) removing any protectinggroups; or iii) forming a pharmaceutically acceptable salt or in-vivohydrolysable ester.